Friedreich ataxia

Friedreich ataxia is a degenerative disorder characterized by a progressive cerebellar ataxia with a lack of deep-tendon reflexes, a pyramidal weakness and dysarthria. Increased heart wall thickness is observed in all patients, and 70% of the patients actually develop a life-threatening hypertrophic cardiomyopathy.

Moreover, 10% of the patients also presented with diabetes mellitus and 20% of the patients had carbohydrate intolerance. Friedreich’s ataxia is a common autosomal recessive disorder with a frequency of 1/50 000 live births.

Friedreich ataxia is an autosomal-recessive progressive illness, generally beginning in the first decade of life with gait ataxia, followed by hand clumsiness and dysarthria. Deep tendon reflexes are depressed or absent, but an extensor plantar reflex is typically present. Joint position and vibratory sense are impaired, and there is sometimes loss of pain and temperature sensation and light touch.

Most patients develop pes cavus and kyphoscoliosis. There is a high incidence of cardiac disease with arrhythmias and congestive heart failure. Concomitant diabetes is found in about 10% of patients. Most patients become wheelchair-bound within about 5 years of onset; the cause of death is intercurrent pulmonary infections and cardiac disease.

Morphology

The spinal cord shows loss of axons and gliosis in the posterior columns, the distal portions of corticospinal tracts, and the spinocerebellar tracts. There is degeneration of neurons in the spinal cord (Clarke column), the brainstem (cranial nerve nuclei VIII, X, and XII), the cerebellum (dentate nucleus and the Purkinje cells of the superior vermis), and to some extent the Betz cells of the motor cortex.

Large dorsal root ganglion neurons are also decreased in number; their large myelinated axons, traveling first in the dorsal roots and then in dorsal columns, therefore undergo secondary degeneration. The heart is enlarged and may have pericardial adhesions.

Multifocal destruction of myocardial fibers with inflammation and fibrosis is detectable in about half the patients who come to autopsy examination.

Genetics

The gene for Friedreich ataxia has been mapped to chromosome 9q13, and in most cases, there is a GAA trinucleotide repeat expansion in the first intron of a gene encoding a protein named frataxin.

Affected individuals inherit abnormal forms of the frataxin gene from both parents and have extremely low levels of the protein.

In some cases of Friedreich ataxia, one of the mutant alleles harbors a missense or nonsense mutation. Frataxin undergoes processing and ends up in the inner mitochondrial membrane, where it has been suggested to play a role in regulation of iron levels.

Because of the need for this metal in many of the complexes of the oxidative phosphorylation chain, mutations in frataxin have been suggested to result in generalized mitochondrial dysfunction.

Thus, Friedreich ataxia shares biologic features with other spinocerebellar ataxias (anatomic distribution of pathology, trinucleotide repeat expansion) and the mitochondrial encephalopathies.

Physiopathology

The disease gene has been mapped on chromosome 9q13 and identified by positional cloning. This gene encodes a 210 amino-acid protein called frataxin.

The mutation responsible for the disease consists of a GAA repeat expansion in the first intron of the frataxin gene present in 98% of the patients and results in a loss of function of frataxin because of impaired gene transcription.

Friedreich ataxia, the most frequent cause of recessive ataxia, is due in most cases to a homozygous intronic expansion resulting in the loss of function of frataxin. Frataxin is a mitochondrial protein conserved through evolution.

Yeast knock-out models and histological data from patient heart autopsies have shown that frataxin defect causes mitochondrial iron accumulation.

Biochemical data from patient heart biopsies or autopsies have revealed a specific deficiency in the activities of aconitases and of mitochondrial iron-sulfur proteins.

These results suggest that frataxin may play a role either in mitochondrial iron transport or in iron-sulfur cluster assembly or transport.

Iron abnormalities suggest a pathogenic mechanism involving free radical production and oxidative stress, a process that might be sensitive to antioxidant therapies.

Etiology

Deficiency of frataxin (FXN) is the cause of Friedrich ataxia. It is a hereditary trinucleotide repeat disease. The expansion of intronic trinucleotide repeat GAA in FXN gene results in Friedreich ataxia.

The causative Friedreich ataxia protein, dubbed frataxin (FXN), has an essential role in mitochondrial iron homeostasis, and Friedreich ataxia can therefore be considered as an OXPHOS homeostasis defect.

Frataxin (FXN) is a small protein, localized to the mitochondrion.

The function of frataxin (FXN) is not entirely clear, but it seems to be involved in assembly of iron-sulfur clusters.

The protein functions in regulating mitochondrial iron transport and respiration.

Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified.

Pathogenesis

Mitochondria obtained from heart biopsies of Friedreich ataxia patients have disclosed specific defects in the citric-acid cycle enzyme aconitase, and complex I-III activities.

References

 Shoubridge EA. Nuclear genetic defects of oxidative phosphorylation. Hum Mol Genet. 2001 Oct 1;10(20):2277-84. PMID: 11673411

 Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet. 2001 May;2(5):342-52. PMID: 11331900

 Rotig A, Sidi D, Munnich A, Rustin P. Molecular insights into Friedreich’s ataxia and antioxidant-based therapies. Trends Mol Med. 2002 May;8(5):221-4. PMID: 12067631

 Puccio H, Koenig M. Recent advances in the molecular pathogenesis of Friedreich ataxia. Hum Mol Genet. 2000 Apr 12;9(6):887-92. PMID: 10767311